Up-regulation of brain cytokines and metalloproteinases 1 and 2 contributes to neurological deficit and brain damage in transient ischemic stroke.

Ischemic stroke represents a major cause of adult death and severe neurological disability worldwide. Reperfusion following brain ischemia produces an inflammatory cascade that increases brain damage. In this context, matrix metalloproteinases (MMPs) play an important role as pro-inflammatory mediators. The MMP 2 up-regulation seems to promote matrix degradation, blood-brain barrier (BBB) disruption and facilitates the influx of peripheral inflammatory cells to the brain after stroke. However, there are not studies about MMP-1 in this condition. The aim of this study is to evaluate the association of brain damage, inflammatory response and the immunostaining profile of matrix metalloproteinases 1 and 2 after transient global cerebral ischemia. Mice were submitted to bilateral common carotid arterial occlusion (BCCAo) during 25 min. After three days of reperfusion, the neurological deficit score was evaluated and the animals were euthanized. Brain samples were collected in order to analyze the histopathological damage, MMPs 1 and 2 immunostaining and cytokines and chemokines levels. Ischemic group showed neurological deficits associated with brain lesions, characterized by necrotic core and penumbra zone three days after reperfusion. Higher brain immunostaining of MMP-1 and MMP-2 was observed in BCCAo samples than in sham samples. Ischemic group also exhibited increased brain levels of the cytokines tumoral necrosis factor (TNF) and interleukin 1ß (IL-1ß), chemokine (C-X-C motif) ligand 1 (CXCL1), and chemokine (C-C motif) ligand 5 (CCL5) in comparison to sham group. Our results suggest that the MMP-1 and MMP-2 raise, associated with the up-regulation of inflammatory mediators, contributes to brain damage and neurological deficits after global brain ischemia followed by three days of reperfusion in mice.

Antitumor effect of selenium-rich Brazil nuts and selenomethionine dietary supplementation on pre-existing 4T1 mammary tumor growth in mice.

Selenium (Se) is an essential micronutrient known to play an important role in the antioxidant system that can potentially influence tumor growth. We aimed to investigate the effects of dietary Se supplementation after detection of 4T1 mammary tumor growth in BALB/c mice. Thirty female mice received subcutaneous inoculation of 4T1 cells. After five days, all animals presenting palpable tumors were randomly assigned to three groups: a control group (Se-control) receiving a diet with adequate Se (0.15 mg/kg) and two other groups that received Se-supplemented diets (1.4 mg/kg of total Se) with either Brazilian nuts (Se-Nuts) or selenomethionine (SeMet). Data were assessed by either One or Two-way ANOVA followed by Tukey's HSD or Bonferroni's post hoc tests, respectively. Both Se-supplemented diets reduced tumor volume from the thirteenth day of feeding compared with the Se-adequate (control) diet (p < 0.05). The SeMet group presented a higher Se blood concentration (p < 0.05) than the Se-control group, with the Se-Nuts group presenting intermediate values. Selenoprotein P gene expression in the liver was higher in the Se-Nuts group than in the Se-control group (p < 0.05), while the SeMet group presented intermediate expression. Dietary Se supplementation, starting after detection of 4T1 palpable lesions, reduced tumor volume in mice.

Epithelial-mesenchymal transition inhibition by metformin reduces melanoma lung metastasis in a murine model.

Melanoma is an aggressive cancer with fast metastatic spread and reduced survival time. One common event during the neoplastic progression is the epithelial-mesenchymal transition (EMT), which enhances invasiveness, cell migration, and metastasis. In this study, we investigated the effects of metformin at EMT in melanoma cell lines B16-F10 and A-375, in vitro, and the impact of EMT downregulation on melanoma progression in vivo. The metformin cells treatment reduces the migration potential in vitro and reduced the development of pulmonary metastases and the expressions of N-cadherin, vimentin, ZEB1, and ZEB2 at the metastases site, in vivo. These results indicate that metformin can promote EMT downregulation impairing the metastatic potential of melanoma cells.